Soluble amidine salts



Patented Feb. 5, 1946 UNITED STATES PATENT OFFICE SOLUBLE AMIDDNE SALTS George Newbery, Hutton Mount, near Brentwood,

' and Alexander Peter Tawse Easson, Homchurch, England, assignors to May & Baker Limited, Dagenham, Essex, England, a British company No Drawing. Application April 11, 1942, Serial No. 438,612. In Great Britain April 25, 1941 9 Claims. (01. 260-501) R represents a benzene radical, and X represents a linkage which may be a single bond or an alkane chain -(CH2)n (where n represents 1 to and in which also one or more of the CH2 groups may be replaced by oxygen, sulphur or the group NH) or X represents a -CR1=CR2 grouping in which R1 and R2 each represents either a hydrogen atom or a hydrocarbon group (e. g., an alkyl, aryl or aralkyl group). Generally, the salts of these diamidines, such as the hydrochlorides, are not very readily soluble in water. It is an obvious therapeutic advantage to have available stable salts possessing a high degree of solubility in water and the present inventlon has for its object the production of such salts. In many instances, therapeutically useful basic compounds have been found to furnish extremely soluble salts with methane-sulphonates, but in the case of the various therapeutically useful amidine compounds, such as 4:4'-diamidinostilbene or 4:4'-diamidino-diphenoxypentane, the dimethane-suphonates are very little more soluble than the hydrochlorides.

We have discovered a new class of salts of the symmetrical aromatic diamidines having the foregoing general formula, which salts are stable and possess a high degree of solubility in water, such salts being the salts with members or the group consisting of hydroxyethane sulphonic acid and hydroxy-propane sulphonic acid.

In'general, these new salts can be prepared by combining the diamidine base or a salt thereof with hydroxy ethane sulphonic acid or hydroxypropane sulphonic acid or with a salt of either of such acids. Specifically, the diamidine base can be directly combined with hydroxy-ethane or hydroxy-propane sulphonlc .acid or with a suitable salt oi either or such acids (e. g., the am- 'monlum salt). Alternatively, the required salts may be formed by producing the diamidine base in situ and in the presence of either one of the said acids or a salt of such acid. Thus, the imino-ether corresponding to the diamidine base may be reacted with the ammonium salt of hydroxy-ethane or hydroxy-propane sulphonic acid. Again, the required salts may be obtained by double decomposition of suitable salt pairs e. g. using the dihydrochloride of the diamidine base and the silver salt of the acid.

Examples of diamidinesv of the foregoing general formula are:4:4'-diamidino-diphenoxy pentane, 4:4-diamidino-diphenoxy propane and 4;4-diamidino-diphenylether, 4:4-diamidinostilbene and 4:4'-diamidino-a,a'-dimethyl-stilbene.

In the following description, there are given, purely by way of illustration, examples of the manufacture of compounds within the scope of the present invention.

Example I acid) and crystallises in prisms (solubility in water approx. 1 in 4 at 20 C.)

Example II 4 :4 -diamidinodiphendxy-pentane-di-hydroxyethane-sulphonate prepared by the method of Example I, using the theoretical amounts of the diamidine and the acid, crystallised as prisms on addition of acetone to the aqueous solution. It contains 2 /gH2O and is soluble in water, approx. 1 in 8 at 20 C.

Eazample III 3.2 grms. of 4:4'-diamidinodiphenoxy propane were dissolved in a slight excess of 4N isethionic acid. The solution was just acid to litmus. It was filtered with charcoal, the solids Washed with a little methanol and the amidine isethionate precipitated from the filtrate and washings by.

adding acetone. The yield of the required 4:4-

2 diamidinodiphenoxy propane di-isethionate was 5.2 grins.

Example IV.

67.2 arms. of 4:4'-diamidinodiphen'ylether were dissolved in a slight excess of 8N isethlonic acid with sufllcient water to give complete solution in the cold. The solution was Just acid to litmus, and to it was added about quarter oiits volume of alcohol. Acetone was, then added slowly and with stirring, so that the amidine isethionate separated in crystalline form. Addition was continued until precipitation was almost complete. The mixture was allowed to stand for some time and the crystals filteredofl, washed with acetone and dried. The yield or the required 4:4'-diamidinodiphenylether di-isethionate was 180 Example V 9.0 grms. of 4:4-diamidino-,'-'dimethylstilbene dihydrochloride were dissolved in a little warm water and slight excess of caustic soda solution added. The diamidine base was precipitated as an oil which solidified on cooling in ice. The base was filtered ofi, washed with water and then while, damp dissolved in a slight excess of 8N .isethionic acid. A little alcohol was added and the required 4:4'-diamidino-a,a-dimethylstilbene di-isethionate precipitated in the formg of buff yellow micro crystals. Yiel 9.8 brms.

Example VI 26 grms. of 4:4'-diamidino stilbene were added in small portions to a gently boiling mixture of 28 grms. (2 mols.) of ammonium isethionate and 250 cos. of 50% alcohol. Ammonia was immediately evolved with the formation of the amidine base which dissolved completely in a few minutes. The reaction was completed by boiling of! the ammonia, whereafter the solution was filtered with charcoal. The required 4:4'-diamidinostil- 'bene di-isethionate was precipitated by slowly adding acetone. Yield about 90%.

Example VII A mixture of stilbene'4:4'-di-iminoethyl-ether (1.6 g.) and finely powdered ammonium p-hydroxy-ethane-sulphonate was suspended in cc.

Example VIII 37.3 grms. of pure 4:4'-diamidinostilbene dinydrochloride hydrate (33.7 grms. of anhydrous salt) were dissolved in 400 ccs.of hot water and a solution of 46.8 grms. of silver isethionate in 100 cos. of water was added with stirring. The mix- 7 ture was heated on. the steam bath for some time to coagulate the silver chloride which precipitated. The precipitate was filtered ofi (charcoal can be used if necessary to clarify) and the solids were concentrated by evaporation'and the required diamidine di-isethionate precipitated in crystalline form by adding a little alcohol, followed by the slow addition of acetone with shaking, until precipitation was complete. The yield obtained was 49 guns. or of theory.

We claim:

1. 4 4' diamidino stil-bene di 3 hydroxy- I ethane-sulphonate.

2. 4:4'-diamidino-a,a'-dimethyl-stilbene-di-phydroxyethane-sulphonate.

3. 4:4'-diamidino-stilbene di 'y-hydroxypropane-sulphonate.

4. A symmetrical compound of the formula NH o=Nn .nmsx Nmamsx in which each R, being selected ,i'rom the group consisting of hydrogen and a lower alkyl radical,

is alike, and in which X is selected from the group consisting oi hydroxy-ethyl and hydroxy-propyl radicals. 1

' 5. Process tor the production of a symmetrical aromatic .dlamidine salt having the Iormula I =NH QNH IkHLHOlBX N H:.HOsSX in which R is selected from the group consisting of hydrogen and a. lower alkyl radical, and in which X is selected from the group consisting of hydroxy-ethyl and hydroxy-propyl radicals, which comprises reacting a compound of the formula .53 7 QNHQNH N HI in which Rhas the aforesaid value, with a member selected from the group consisting of'p-hydroxy-ethane-sulphonic acid, y-hydroxypro- 8. Process for the production of 4:4'-di'amiwashed with water. The filtrate and washings 78 dino-stilbene-di-p hydroxyethane sulphonate,

I 2,304,003 r 3 which comprises reacting-4:4'-diamidino-stiibene which comprisesreacting a symmetricai comwith ammonium-p-hydroxy-ethane-su1phonate. pound of the formula 9. Process for the production of a symmetrical R aromatic diamidine salt having the formula a 1 1m NH, m in which R has the aforesaid value, with a memllmmofix Nmflmsx ber selected from the group consisting oi p-hy- .droxy-ethane-sulphonic acid, 'y-hydroxy-proin which R is selected from the group consisting pane-sulphonic acid, and the ammonium salt of a of hydrogen and a lower alkyl radical, and in said acid. which X is selected from the group consisting of GEORGE NEWBERY. hydroxy-ethyl and hydroxy-propyl radicals. ALEXANDER PETER TAWSE EASSON. 

